1. Field of Invention:
This invention relates to processes for preparing rimantadine and more particularly to low temperature and pressure processes from 1-adamantyl methyl ketoxime.
2. Prior Art:
Pharmaceutical compositions containing .alpha.-methyl-1-adamantanemethylamine or the hydrochloride salt thereof (both herein referred to as rimantadine) are useful antiviral agents in animals. Rimantadine and related compounds useful as antivirals were first described by Prichard in U.S. Pat. Nos. 3,352,912 and 3,592,934. Both patents describe the preparation of rimantadine from the corresponding ketone oxime by reduction with lithium aluminum hydride. This preparation is also described in Aldrich et al., J. Med. Chem., 14, 535 (1971). Although this procedure is satisfactory in the laboratory, the high cost of this reducing agent and the danger of handling it on a large scale make this process unappealing as a commercial process.
Brake in U.S. Pat. No. 3,489,802 describes the preparation of rimantadine by the reductive amination of the corresponding acetyl compound. In this process, the acetyl compound, hydrogen, ammonia and catalyst (cobalt, ruthenium, or nickel) are reacted at temperatures up to 250.degree. C., e.g., 140.degree.-250.degree. C., and pressures up to 15,000 psi, e.g., 500-2000 psi. This process on a commercial scale would require expensive, special reductive amination equipment.
Another rimantadine preparation process is described by Polis and Grava in U.S. Pat. No. 3,852,352. This is a Leuckart-Wallach reaction in which rimantadine is prepared by reacting 1-adamantyl methyl ketone with ammonium formate, formamide, or a mixture of formamide or acetamide with formic acid. Generally, yeilds are low (up to 82% by weight) and workup is tedious.
Shetty in U.S. Pat. No. 4,100,170 describes the reduction of 1-adamantyl-2-propanone oxime with hydrogen at 40 psig over PtO.sub.2 in acetic acid. PtO.sub.2 as a catalyst, however, has several disadvantages such as lower yield, higher cost and slower reaction which make it unsatisfactory for use in the preparation of rimantadine.
There is a need in the art for a high yield, low cost and safe process for the manufacture of rimantadine.